Piperazine, piperidine and tetrahydropyridine derivatives and their pharmaceutical use

ABSTRACT

Novel piperazine, piperidine and tetrahydropyridine derivatives comprising a dibenzofurane moiety are provided herein, as well as pharmaceutical compositions comprising same and therapeutic uses thereof.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to a novelfamily of compounds and uses thereof to treat disorders such as centralnervous system disorders, and more particularly, but not exclusively,novel compounds comprising a piperazine, piperidine ortetrahydropyridine moiety.

Piperazine derivatives which act on the central nervous system (CNS) areknown in the art. For example, EP 512755 describes piperazinederivatives having high binding affinity to 5-HT receptors. Recently,piperazine derivatives (and also other nitrogen-containing six-memberedrings, such as piperidine), which are substituted at positions 1 and 4with a fused ring heterocyclic and phenyl groups, respectively, weredescribed in WO 08/117269. The compounds disclosed in WO 08/117269 arereported to bind to dopamine and 5-HT receptors and to be useful in thetreatment of various CNS disorders.

DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The invention relates to a class of compounds of formula (I):

wherein:

-   -   Y₁ and Y₂ are independently CH, C(R₁) or N;    -   X is N, CH or C, with the proviso that when X is C, then the        broken line represents a chemical bond;    -   R₁, R₂ and R₃ are independently selected from the group        consisting of C1-C5 alkyl, —OH, —SH, halogen, alkoxy, namely,        —O(C1-C5alkyl), —NR₄2, NO₂, —CN.    -   m is 0, 1, 2, 3, 4 or 5;    -   n is 0, 1, 2 or 3; and    -   p is 0, 1, 2, 3 or 4.

It is understood that when m, n, or p equals 0, then the free positionsat the relevant ring are occupied by hydrogen atoms.

The compounds of formula I have been found to posses high bindingaffinity for dopamine and serotonin receptors. The compounds areaccordingly useful in the treatment of various CNS disorders, asdiscussed in more detail below.

Preferably, X in formula I is nitrogen. More specifically, preferredsub-classes of compounds provided by the present invention arerepresented by formulas Ia, Ib, Ic, Id and Ie (in the formulas depictedbelow, the substituents on the dibenzofuran system have the meanings asset forth above):

wherein m is 0, 1, 2 or 3, more preferably 0, 1 or 2, and when m isother than 0, then R₁ is preferably selected from the group consistingof hydroxy, alkoxy (specifically —OCH3 or —OC2H5), halogen and cyano.

The compounds of formula I may be prepared by reacting a piperazine,piperidine or 1,2,3,6-tetrahydropyridine derivative of formula II (or anacid addition salt thereof),

with dibenzofurane of formula III:

wherein X, Y1, Y2, R1, R2, R3 m, n and p are as hereinabove defined andL is a suitable leaving group such as halogen, (specifically chlorine orbromine), p-toluene sulfonate or mesylate). Thus, the reaction involvesthe formation of a tertiary amine by alkylation of a secondary amine (offormula II) with alkyl halide, tosylate or mesylate (of formula III).The reaction may be conveniently carried out in a solvent, which may beselected from the group consisting of dimethylformamide; ethers suchtetrahydrofuran; acetonitrile, ketones such as acetone and methyl ethylketone; and halogenated hydrocarbons. The reaction is carried out in thepresence of a base, which may be either an inorganic base (alkali oralkaline earth metal carbonate, alkali metal hydrogen carbonate andsodium hydroxide) or an organic base (trialkyl amine, such astriethylamine; or pyridine). dimethylformamide and triethylamine aregenerally the preferred solvent and base, respectively, employed in thereaction.

In practice, the solvent and the base are charged into a reactionvessel, following which the starting materials of formulas II and IIIare added and allowed to dissolve under stirring. The starting materialsmay be used in equimolar amounts, but it may be preferable to apply thestarting material of formula II in a 1.5 molar excess. The reaction maybe carried out under room temperature or possibly under heating. Thereaction reaches completion after about 16 hours. The product of formulaI may then be isolated from the reaction mixture by means of knownprocedures. More specifically, upon removal of the solvent by means ofevaporation under reduced pressure, an the product of formula I may berecovered as an oily material which can be purified by means of silicagel column chromatography.

The reactants of formula II and III which participate in the syntheticpathway described above are commercially available, or may be preparedby conventional methods.

Regarding the starting material of formula III, a dibenzofurane systemis most generally represented by the following formula:

where the numbers 1-4 and 6-9 represent positions in which substiuentsmay be provided. As indicated before, in the starting material offormula III, which is operative according to the present invention inthe preparation of the end product of formula I, position 4 is occupiedby the group —CH2L (wherein L is a leaving group). The starting materialof formula III may be obtained by reducing a corresponding aldehyde, toform a dibenzofurane derivative having —CH2OH group attached at position4, and subsequently converting said alcohol to the starting material offormula III, wherein the leaving group L is halogen, such as chlorine orbromine, as illustrated by the following sequential reaction scheme:

The reduction of the aldehyde of formula (V) to form the primary alcoholof formula (IV) may be conveniently accomplished in the presence of ahydride source, namely, a complex metal hydride, such as sodiumborohydride or lithium aluminum hydride. A suitable solvent to employedin the reaction is typically a short chain alkanol, specificallymethanol or ethanol. The primary alcohol intermediate is isolated fromthe reaction mixture and is subsequently treated with a halide source,such as thionyl chloride or various phosphorous halides. The conversionof the alcohol (IV) into the corresponding haloalkane (III).

The compounds the invention were tested for dopamine (D2, D3 and D4.4)receptors binding activity and 5-HT_(1A) receptor binding activityaccording to the procedures described in WO 08/117269; the compounds ofthe invention were found to be potent ligands of said receptors. Thecompounds of the invention may be used in the treatment of CNS disordersin mammals, especially human. Of particular interest is the use of thecompounds of the invention as anti-dyskinetic agents. Dyskinesia is aserious side effect associated with L-DOPA treatment of patients withParkinson's disease. An in vivo study given below demonstrates that thecompounds of the invention exhibit activity against L DOPA induceddyskinesia in parkinsonian rats.

The invention also provides a pharmaceutical composition comprising thecompound of formula (I) or a pharmaceutically acceptable salt thereof incombination with one or more pharmaceutically acceptable carriers. Thecomposition may be provided either in a solid or liquid form, or amixture of solid and liquid.

Suitable solid compositions include tablets, capsules, caplets, powders,granulates, sachets, lozenges and pastilles. Examples of excipientswhich are combined with the active ingredient to produce the compositioninclude (but are not limited to) diluents or fillers (e.g. lactose,microcrystalline cellulose, pregelatinized starch), binders (e.g.carbopol, povidone, xanthan gum), lubricants (e.g. magnesium stearate),glidants (e.g. talc, colloidal silicon dioxide) and disintegrants (e.g.alginic acid, carboxymethylcellulose, carboxymethyl starch,croscarmellose sodium, sodium starch glycolate).

Solid unit dosage forms (e.g., tablets or capsules) may be manufacturedby a variety of different methods, as are well known in the art,including a direct compression using a tablet punch. As an alternativeto direct compression, the active ingredient and excipients may becombined by dry blending, and then subjected to dry granulation prior totablet compression. A further alternative method is to utilize wetgranulation, in which at least some of the excipients, together with theactive ingredient, are blended and then further mixed in the presence ofa granulation liquid. Following aggregation of the various powders, theaggregates (i.e. granules) are then sized by screening or milling, driedand used to produce a tablet. The tablet may be finally coated.

Solid formulation blends for loading into capsules (such as soft gelatincapsules) may be prepared by dry blending, or by wet or dry granulationprior to being introduced into said capsules.

Suitable liquid compositions include, inter alia, solutions, suspensionsand syrups, in which solvents (e.g. water, an organic solvent)emulsifying agents (e.g. carbomer, cetyl alcohol, gelatin), flavoringagents (e.g. vanillin, fruit acids, menthol), sweeteners (e.g.

sucrose, fructose, aspartame, saccharin) and preservatives may bepresent together with the active compound of formula I.

In addition to orally-administrable compositions, the compounds of theinvention may be formulated into sterile solution for intravenous orintramuscular injection.

Further information relating to the preparation of solid, liquid and geldosage forms that are suitable for use in the present invention may beobtained from any standard pharmaceutical reference work, such asRemington's Pharmaceutical Science (Martin E W [1995], Mack PublishingCompany, 19th ed.).

A further aspect of the invention relates to the use of a compound offormula I set forth herein above in the preparation of a medicament,e.g., for the treatment of CNS disorders in a mammal, and morespecifically, for the treatment of dyskinesia.

The present invention also relates to a method for treating CNSdisorders in a patient, comprising administering a therapeuticallyeffective amount of a compound of formula I. It is to be understood thatthe dosages may vary depending upon the requirements of the patient, theseverity of the disorder being treated, and the particular compoundbeing used. If desired, the daily dose may also be divided into multipledoses for administration, e.g., two to four times per day. The compoundsof Formula I according to this invention may be administered orally orparenterally.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the results of an in vivo activity studyin which a compound of the invention was tested as an anti-diskinesiaagent.

EXAMPLES Preparation 1 Preparation of 4-(chloromethyl) Dibenzofuran (AStarting Material of Formula III)

a) Dibenzofuran-4-ylmethanol

1 g (5.1 mmol) of Dibenzofuran-4-carboxaldehyde is dissolved in 5 ml ofethanol. 0.24 g of NaBH₄ is then added portionwise to the stirredsolution during a period 20 minutes. The solution is maintained understirring at room temperature for 2 hours, following which the solvent isevaporated. The residue obtained is treated with water, and aqueouslayer is then extracted with ether. Evaporation of the organic phaseyielded 0.90 g of Dibenzofuran-4-ylmethanol.

b) 4-(chloromethyl) Dibenzofuran

Thionyl chloride (6 ml) is added to a solution ofDibenzofuran-4-ylmethanol (0.9 g). The solution is refluxed for 1 hour.Excess of reagent is evaporated to yield 4-(chloromethyl) Dibenzofuran(0.97 g).

Example 1 (L32)

4-(chloromethyl) Dibenzofuran (0.34 g, 1.7 mmol) and1-(2-ethoxyphenyl)piperazine hydrochloride (0.62 g, 2.55 mmol) are addedto a stirred solution of N,N Dimethylformamide (5 ml) and triethylamine(1 ml). The solution formed is stirred at room temperature for 24 hours.The solvent is then evaporated under reduced pressure and the cruderesidue obtained was chromatographed on silica gel with eluanthexane:ethyl acetate (90% Hexane/10% Ethyl Acetate). Followingrecrystallization from hexane, the product was collected in a solid form(120 mg).

H¹NMR: 1.10 (t, 3H), 2.82 (t, 2H), 3.27 (t, 2H), 4.02 (s, 2H), 4.21 (q,2H) 7.10-8.05 (m, 10H, arom).

Example 2 (L33)

4-(chloromethyl) Dibenzofuran (0.34 g, 1.7 mmol) and 1-(3-hydroxyphenyl)piperazine (0.50 gr. (2.55 mmol) are added to a stirred solution of N,NDimethylformamide (5 ml) and triethylamine (1 ml). The solution formedis stirred at room temperature for 24 hours. The solvent is thenevaporated under reduced pressure and the crude residue obtained ischromatographed on silica gel with eluant hexane:ethyl acetate (80%Hexane/20% Ethyl Acetate). Following recrystallization from hexane, theproduct is collected in a solid form (390 mg).

H¹NMR: 2.84 (t, 2H), 3.31 (t, 2H), 4.07 (s, 2H), 6.92 -7.91 (m, 11H,arom).

Example 3 (L34)

4-(chloromethyl) Dibenzofuran (0.34 g, 1.7 mmol) and4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (0.50 g) are added toa stirred solution of N,N Dimethylformamide (5 ml) and triethylamine (1ml). The solution formed is stirred at room temperature for 24 hours.The solvent is then evaporated under reduced pressure and the cruderesidue obtained is chromatographed on silica gel with eluanthexane:ethyl acetate (90% Hexane/10% Ethyl Acetate). Followingrecrystallization from hexane, the product is collected in a solid form(100 mg).

H¹NMR: 2.78-3.95 (m, 6H,), 4.03 (s, 2H), 4.55 (m, 1H) (6.93-8.82 (m,12H, arom)

Example 4 (L105)

4-(chloromethyl) Dibenzofuran (1 g, 5 mmol) and 4-phenyl piperidine (1.2g, 7.55 mmol) are added to a stirred solution of N,N Dimethylformamide(10 ml) and triethylamine (2 ml). The solution formed is stirred at roomtemperature for 24 hours. The solvent is then evaporated under reducedpressure and the crude residue obtained is chromatographed on silica gelwith eluant hexane:ethyl acetate (90% Hexane/10% Ethyl Acetate) to givethe product (195 mg)

H¹NMR: 2.18-3.88 (m, 9H, piperidine), 4.03 (s, 2H), (6.90-8.72 (m, 12H,arom)

Example 5 (L106)

4-(chloromethyl) Dibenzofuran (0.78 g, 4 mmol) and 2-thiazole piperazine(1 g, 6 mmol) are added to a stirred solution of N,N Dimethylformamide(10 ml) and triethylamine (2 ml). The solution formed is stirred at roomtemperature for 24 hours. The solvent is then evaporated under reducedpressure to give a crude residue, which is chromatographed on silica gelwith eluant hexane:ethyl acetate (90% Hexane/10% Ethyl Acetate) toafford the product (204 mg).

H¹NMR: 2.86 (t, 2H), 3.28 (t, 2H), 4.03 (s, 2H), (6.92-8.89 (m, 9H,arom)

Example 6 (L107)

4-(chloromethyl) Dibenzofuran (0.78 g, 4 mmol) and 1-(-2-methoxyphenyl)piperazine hydrochloride (1.4 g, 6 mmol) are added to a stirred solutionof N,N Dimethylformamide (10 ml) and triethylamine (2 ml). The solutionformed is stirred at room temperature for 24 hours. The solvent is thenevaporated under reduced pressure to give a crude residue, which ischromatographed on silica gel with eluant hexane:ethyl acetate (90%Hexane/10% Ethyl Acetate) to afford the product (411 mg).

H¹NMR: 2.81 (t, 2H), 3.21 (t, 2H), 4.02 (s, 2H), 4.21 (s, 3H) 7.09-8.09(m, 10H, arom).

Example 7 (L108)

4-(chloromethyl) Dibenzofuran (0.78 g, 4 mmol) and 1-(-2-pyridyl)piperazine (0.8 g, 5 mmol) are added to a stirred solution of N,NDimethylformamide (10 ml) and triethylamine (2 ml). The solution formedis stirred at room temperature for 24 hours. The solvent is thenevaporated under reduced pressure to give a crude residue, which ischromatographed on silica gel with eluant hexane:ethyl acetate (80%Hexane/20% Ethyl Acetate) to afford the product (223 mg).

H¹NMR: 2.87 (t, 2H), 3.25 (t, 2H), 4.1 (s, 2H), 7.09-8.17 (m, 10H,arom).

Example 8 (L109)

4-(chloromethyl) Dibenzofuran (0.78 g, 4 mmol) and 1-(-2-cyanophenyl)piperazine (0.9 g, 5 mmol) are added to a stirred solution ofN,N-Dimethylformamide (10 ml) and triethylamine (2 ml). The solutionformed is stirred at room temperature for 24 hours. The solvent is thenevaporated under reduced pressure to give a crude residue, which ischromatographed on silica gel with eluant hexane:ethyl acetate (90%Hexane/20% Ethyl Acetate) to afford the desirable product (180 mg)

H¹NMR: 2.86 (t, 2H), 3.28 (t, 2H), 4.05 (s, 2H), 6.96-7.97 (m, 11H,arom).

Example 9 (L110)

4-(chloromethyl) Dibenzofuran (0.78 g, 4 mmol) and 1-(-2-pyrimidyl)piperazine (1 g, 6 mmol) are added to a stirred solution of N,NDimethylformamide (10 ml) and triethylamine (2 ml). The solution formedis stirred at room temperature for 24 hours. The solvent is thenevaporated under reduced pressure to give a crude residue, which ischromatographed on silica gel with eluant hexane:ethyl acetate (80%Hexane/20% Ethyl Acetate) to afford the product (503 mg)

H¹NMR: 2.84 (t, 2H), 3.27 (t, 2H), 4.1 (s, 2H), 7.04-8.27 (m, 9H, arom).

Example 10

The compounds of Examples 1, 3, 4 and 9 were tested for their 5-HT_(1A)receptor binding activity and dopamine (D2, D3 and D4.4) receptorsbinding activity according to the protocols set forth above. Thepercentage inhibition of labeled ligand binding caused by the indicatedfew test ligand compound of the invention at different concentrations ofsaid test ligand is shown in Table I.

TABLE I Compound, 1 micrMol 5-HT_(1A) binding D2 binding D3 binding D4binding L-33 43.4 75% 78.2 77.7 L-109 73.5 68.7 63.2 64.9 L-107 86.7 96%33.7 78 L-105 42.2 93.8 44.5 69.1

The results demonstrate that the compounds of the invention stronglybind to both D2, D3 and D4 dopamine and 5-HT_(1A) receptors.

Example 11

In the following study, the compound of Example 2 was tested for its invivo activity against L-DOpA induced dyskinesia in parkinsonian rats(the model is the L-DOPA-induced abnormal involuntary movements (AIMS)in the 6-hydroxydopamine (6-OHDA) lesion rat model).

Rats were unilaterally lesioned with (6-OHDA) in medial forebrainbundle. Three weeks later, rats were injected with apomorphine (0.1mg/kg s.c.) and numbers of contralateral turns were counted using arotameter. Two weeks after the apomorphine test, rats showing markedturning activity were selected and split into 2 groups:

The experimental group, which received the compound of Example 2, andthe control group, which received the injection medium for said compound(CMC in saline); n=5 and 3 respectively.

All animals were treated daily with L-dopa/carbidopa (25/6 mg/kgrespectively) and dyskinetic movements were scored commencing day 5.Compounds were administered in escalating dose, at daily doses shownbelow, commencing day 11 of L-dopa treatment: 1 mg/kg -11^(th) day, 1mg/kg-12^(th), 2 mg/kg-15^(th), 2 mg/kg-16^(th). On the 17^(th) day, therats of the control group were injected with propranolol (10 mg/kg insaline), whereas the rats of the experimental group were injected withsaline. On the 18^(th) and 19^(th) day all rats were treated withL-dopa/carbidopa only.

The following dyskinetic movements were scored: dystonic posturing, headand upper body movements, forelimb, locomotion, trunk, orolingual.Movements were scored according to the protocol shown in Table II.

TABLE II HEAD AND OROLINGUAL DYSTONIC UPPER BODY LIMB LOCOMOTIVE &OROFACIAL SCORE POSTURING MOVEMENTS MOVEMENTS MOVEMENTS MOVEMENTS 0-4head and body head abnormal, locomotion empty jaw turning towardsmovements purposeless movements movements, the side and movementscontralaterally to contralateral contralateral choreiform of theforelimb the lesion tongue to the lesion twisting and digits protrusionof the neck contralateral to tremor of face and upper the lesionmuscles, body gritting of the teeth 0 absent of movements absent ofmovements single opening   0.5 light or single very weak or weakforelimb ~1 rotation of the mouth, very turning of the single swings in1 minute single tongue weak head towards head single tongue or the sidemovements protrusion, single contralateral tremor of face movements tothe lesion muscles, with angle gritting of teeth of bias about 30° 1turning of the frequent little forelimb ~2-5 hardly seen, but weak headhead movements rotations permanent movements at the point of movementsalong in 1 minute jaw movements the forelimb the ground of with (angleof bias the case close mouth, about 90°) or distinct, rare tongue butrare protrusion movements with lifted forelimb 2 turning of the moderateand steady moderate ~6-10 permanent jaw moderate head distinctly seenmovements rotations movements movements at the point of head with liftedin 1 minute with a little the back paw movements and forelimb opening(angle of bias choreiform mouth, about 150°) twisting more often of theneck tongue protrusion 3 turning of the strong head fast plentiful~11-18 permanent jaw strong head movements movements rotations movementsmovements at the point of and choreiform with lifted in 1 minute with abroadly the tail twisting forelimb opening (angle of bias of the neckand mouth, about 180°) upper body frequent tongue protrusion 4 turningof the strong head rapid more than very head movements, movements of 18rotations strong over the tail choreiform lifted forelimb in a minutemovements with the twisting with large scale angle bias of the neck morethan 180° and upper body, throwing back the head

The results are presented in FIG. 1, AIM score is shown for the relevanttreatment days (for the sum of all movements indicated in Table IItogether). A strong anty-dyskinetic effect is observed on the 16^(th)day, in which day the compound of the invention was administered (forthe second time in succession) at a daily dose of 2 mg/kg. It is notedthat Propanolol, which was given to the control group in a dose of 10mg/kg on the 17^(th) day, reduced the abnormal involuntary movements.

1-23. (canceled)
 24. A compound of formula Id or Ie:

wherein: R₁, R₂ and R₃ are independently selected from the groupconsisting of C1-C5 alkyl, —OH, —SH, halogen, alkoxy, NO₂, and —CN; m is0, 1, 2, 3, 4 or 5; n is 0, 1, 2 or 3; and p is 0, 1, 2, 3 or
 4. 25. Acompound according to claim 24, wherein m is 0, 1, 2 or 3, and when m isother than 0, then R₁ is selected from the group consisting of hydroxy,alkoxy, halogen and cyano.
 26. A pharmaceutical composition comprising acompound as defined in claim 24 in combination with one or morepharmaceutically acceptable carriers.
 27. A method for treating CNSdisorder in mammals, comprising administering to said mammal atherapeutically effective amount of the compound defined in claim 24.28. The method of claim 27, wherein the CNS disorder is dyskinesia. 29.A compound of formula I(a):

wherein: R₂ and R₃ are independently selected from the group consistingof C1-C5 alkyl, —OH, —SH, halogen, alkoxy, NO₂, and —CN; m is 0, 1, 2 or3, and when m is other than 0, then R₁ is hydroxy; n is 0, 1, 2 or 3;and p is 0, 1, 2, 3 or
 4. 30. A pharmaceutical composition comprising acompound as defined in claim 29 in combination with one or morepharmaceutically acceptable carriers.
 31. A method for treating CNSdisorder in mammals, comprising administering to said mammal atherapeutically effective amount of the compound defined in claim 29.32. The method of claim 31, wherein the CNS disorder is dyskinesia. 33.A compound of formula I:

wherein: Y₁ and Y₂ are independently CH, C(R₁) or N; X is N, CH or C,with the proviso that when X is C, then the broken line represents achemical bond; R₁, R₂ and R₃ are independently selected from the groupconsisting of C1-C5 alkyl, —OH, —SH, halogen, alkoxy, NO₂, and —CN; m is0, 1, 2, 3, 4 or 5; n is 0, 1, 2 or 3; and p is 0, 1, 2, 3 or
 4. 34. Acompound according to claim 33, wherein X is N.
 35. A compound accordingto claim 34, having the formula Ia, Ib or Ic:


36. A compound according to claim 33, having the formulas Id or Ie:


37. A compound according to claim 35, wherein m is 0, 1, 2 or 3, andwhen m is other than 0, then R₁ selected from the group consisting ofhydroxy, alkoxy, halogen and cyano.
 38. A pharmaceutical compositioncomprising a compound as defined in claim 33 in combination with one ormore pharmaceutically acceptable carriers.
 39. A method for treating CNSdisorder in mammals, comprising administering to said mammal atherapeutically effective amount of the compound defined in claim 33.40. The method of claim 39, wherein the CNS disorder is dyskinesia.